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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Infect. Dis. 2018, 4, 4, 549-559
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Biological Studies and Target Engagement of the 2-C-Methyl-d-Erythritol 4-Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1R,3S)-MMV008138 and Analogs

  • Maryam Ghavami
    Maryam Ghavami
    Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Hahn Hall South, 800 West Campus Drive, Blacksburg, Virginia 24061, United States
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  • Emilio F. Merino
    Emilio F. Merino
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
    Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases (CTEGD), University of Georgia, 120 Green Street, Athens, Georgia 30602, United States
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    • , 
  • Zhong-Ke Yao
    Zhong-Ke Yao
    Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Hahn Hall South, 800 West Campus Drive, Blacksburg, Virginia 24061, United States
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    • , 
  • Rubayet Elahi
    Rubayet Elahi
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
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    • , 
  • Morgan E. Simpson
    Morgan E. Simpson
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
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    • , 
  • Maria L. Fernández-Murga
    Maria L. Fernández-Murga
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
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  • Joshua H. Butler
    Joshua H. Butler
    Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases (CTEGD), University of Georgia, 120 Green Street, Athens, Georgia 30602, United States
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    • , 
  • Michael A. Casasanta
    Michael A. Casasanta
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
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    • , 
  • Priscilla M. Krai
    Priscilla M. Krai
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
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  • Maxim M. Totrov
    Maxim M. Totrov
    Molsoft LLC, 11199 Sorrento Valley Road, San Diego, California 92121, United States
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  • Daniel J. Slade
    Daniel J. Slade
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
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    Orcidhttp://orcid.org/0000-0001-5634-7220
    • , 
  • Paul R. Carlier*
    Paul R. Carlier
    Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Hahn Hall South, 800 West Campus Drive, Blacksburg, Virginia 24061, United States
    *E-mail: [email protected]. Tel.: 540-231-9219. Fax: 540-231-3255 (P.R.C.).
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    Orcidhttp://orcid.org/0000-0002-6683-285X
    • , and 
  • Maria Belen Cassera*
    Maria Belen Cassera
    Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Engel Hall, 340 West Campus Drive, Blacksburg, Virginia 24061, United States
    Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases (CTEGD), University of Georgia, 120 Green Street, Athens, Georgia 30602, United States
    *E-mail: [email protected]. Tel.: 706-542-5192. Fax: 706-542-1738 (M.B.C.).
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    Orcidhttp://orcid.org/0000-0001-6341-3169
Cite this: ACS Infect. Dis. 2018, 4, 4, 549–559
Publication Date (Web):October 26, 2017
https://doi.org/10.1021/acsinfecdis.7b00159
Copyright © 2017 American Chemical Society
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Abstract

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Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsinfecdis.7b00159.

  • Synthetic procedures and analytical characterization data for all the new compounds described in the paper, SDS-PAGE analysis of the PfIspD used for enzyme inhibition studies (Figure S1), and determination of kinetic parameters for PfIspD (Figure S2) (PDF)

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Cited By

This article is cited by 10 publications.

  1. Varun Gorki, Rahul Singh, Neha Sylvia Walter, Upma Bagai, Deepak B. Salunke. Synthesis and Evaluation of Antiplasmodial Efficacy of β-Carboline Derivatives against Murine Malaria. ACS Omega 2018, 3 (10) , 13200-13210. https://doi.org/10.1021/acsomega.8b01833
  2. Sen Wang, Muxiao Li, Xiaoying Luo, Long Yu, Zheng Nie, Qin Liu, Xiaomeng An, Yangsiqi Ao, Qin Liu, Jiaxu Chen, Yu Tian, Junlong Zhao, Lan He. Inhibitory Effects of Fosmidomycin Against Babesia microti in vitro. Frontiers in Cell and Developmental Biology 2020, 8 https://doi.org/10.3389/fcell.2020.00247
  3. Ivana Perković, Silvana Raić-Malić, Diana Fontinha, Miguel Prudêncio, Lais Pessanha de Carvalho, Jana Held, Tana Tandarić, Robert Vianello, Branka Zorc, Zrinka Rajić. Harmicines − harmine and cinnamic acid hybrids as novel antiplasmodial hits. European Journal of Medicinal Chemistry 2020, 187 , 111927. https://doi.org/10.1016/j.ejmech.2019.111927
  4. Ana Lisa Valenciano, Maria L. Fernández-Murga, Emilio F. Merino, Nicole R. Holderman, Grant J. Butschek, Karl J. Shaffer, Peter C. Tyler, Maria Belen Cassera. Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor. Scientific Reports 2019, 9 (1) https://doi.org/10.1038/s41598-019-50319-5
  5. Marco Biddau, Lilach Sheiner. Targeting the apicoplast in malaria. Biochemical Society Transactions 2019, 47 (4) , 973-983. https://doi.org/10.1042/BST20170563
  6. Kristýna Cagašová, Maryam Ghavami, Zhong-Ke Yao, Paul R. Carlier. Questioning the γ-gauche effect: stereoassignment of 1,3-disubstituted-tetrahydro-β-carbolines using 1 H– 1 H coupling constants. Organic & Biomolecular Chemistry 2019, 17 (27) , 6687-6698. https://doi.org/10.1039/C9OB01139K
  7. Arnau Biosca, Lorin Dirscherl, Ernest Moles, Santiago Imperial, Xavier Fernàndez-Busquets. An ImmunoPEGliposome for Targeted Antimalarial Combination Therapy at the Nanoscale. Pharmaceutics 2019, 11 (7) , 341. https://doi.org/10.3390/pharmaceutics11070341
  8. Alicia A. DeColli, Melanie L. Johnston, Caren L. Freel Meyers. Recent Insights Into Mechanism and Structure of MEP Pathway Enzymes and Implications for Inhibition Strategies. 2019,,https://doi.org/10.1016/B978-0-12-409547-2.14710-9
  9. P. Chellapandi, R. Prathiviraj, A. Prisilla. Molecular evolution and functional divergence of IspD homologs in malarial parasites. Infection, Genetics and Evolution 2018, 65 , 340-349. https://doi.org/10.1016/j.meegid.2018.08.013
  10. Gagandeep Singh Saggu, Shilpi Garg, Zarna Rajeshkumar Pala, Sanjay Kumar Kochar, Vishal Saxena. Deciphering the role of IspD (2‑C‑methyl‑D‑erythritol 4‑phosphate cytidyltransferase) enzyme as a potential therapeutic drug target against Plasmodium vivax. Gene 2018, 675 , 240-253. https://doi.org/10.1016/j.gene.2018.06.084

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